| Summary: | During the last two decades, next-generation sequencing (NGS) has played a key role in enhancing non-small cell lung cancer treatment paradigms through the application of “targeted therapy” in advanced and metastatic disease. The use of specific tyrosine kinase inhibitors in patients with oncogenic driver alterations, such as <i>EGFR</i>, <i>ALK</i>, <i>ROS1</i>, <i>BRAF</i> V600E, <i>MET</i>, and <i>NTRK</i> mutations, among others, has changed treatment approaches and improved outcomes in patients with late-stage disease. Although NGS technology has mostly been used in the setting of systemic therapy to identify targets, response to therapy, and mechanisms of resistance, it has multiple potential applications for patients with earlier-stage disease, as well. In this review, we discuss the emerging role of NGS technologies to better understand tumor biology in patients with non-small cell lung cancer who are undergoing surgery with curative intent. In this patient cohort, we examine tumor heterogeneity, the underlying tumor genomics associated with lung adenocarcinoma subtypes, the prediction of recurrence after complete surgical resection, the use of plasma circulating tumor DNA for detection of early cancers and monitoring for minimal residual disease, the differentiation of separate primaries from intrapulmonary metastases, and the use of NGS to guide induction and adjuvant therapies.
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